The present invention relates to a hemostatic sandwich bandage which comprises a plurality of layers that contain resorbable materials and/or coagulation proteins. The inventive hemostatic sandwich bandage is useful for the treatment of wounded tissue.
The control of hemorrhage (bleeding) is a critical step in first aid and field trauma care. Unfortunately, the materials and methods available to stop bleeding in prehospital care (gauze dressings, direct pressure, and tourniquets) have not changed greatly in the past 2000 years. L. Zimmerman et al., Great Ideas in the History of Surgery (San Francisco, Calif.: Norman Publishing; 1993), 31. Even in good hands they are not uniformly effective, and the occurrence of excessive bleeding or fatal hemorrhage from an accessible site is not uncommon. J. M. Rocko et al., J. Trauma 22:635 (1982).
Mortality data from Vietnam indicates that 10% of combat deaths were due to uncontrolled extremity hemorrhage. SAS/STAT Users Guide, 4th ed. (Cary, N.C.: SAS Institute Inc; 1990). Up to one third of the deaths from exsanguination during the Vietnam War could have been prevented by the use of effective field hemorrhage control methods. SAS/STAT Users Guide, 4th ed. (Cary, N.C.: SAS Institute Inc; 1990).
Although civilian trauma mortality statistics do not provide exact numbers for prehospital deaths from extremity hemorrhage, case and anecdotal reports indicate similar occurrences. J. M. Rocko et al., J. Trauma 22:635 (1982). These data suggest that a substantial increase in survival can be effected by the prehospital use of a simple and effective method of hemorrhage control.
Liquid fibrin sealants have been used for years as an operating room adjunct for hemorrhage control. J. L. Garza et al., J. Trauma 30:512-513 (1990); H. B. Kram et al., J. Trauma 30:97-101(1990); M. G. Ochsner et al., J. Trauma 30:884-887 (1990); T. L. Matthew et al., Ann. Thorac. Surg. 50:40-44 (1990); H. Jakob et al., J. Vasc. Surg., 1:171-180 (1984). The first mention of tissue glue used for hemostasis dates back to 1909. Current Trends in Surgical Tissue Adhesives: Proceedings of the First International Symposium on Surgical Adhesives, M. J. MacPhee et al., eds. (Lancaster, Pa.: Technomic Publishing Co; 1995). The widespread use of fibrinogen and thrombin was common in the last year of World War II, but was abandoned because of the transmission of hepatitis. D. B. Kendrick, Blood Program in WW II (Washington. D.C.: Office of the Surgeon General, Department of Army; 1989). 363-368.
Currently, single donor fibrin sealants are widely used clinically, not only for hemorrhage control but in various surgical situations. W. D. Spotnitz, Thromb. Haemost. 74:482-485 (1995); R. Lerner et al., J. Surg. Res. 48:165-181 (1990). Even more extensive use is limited by the strict requirements for temperature control, availability of thawed blood components, and the need for mixing of components. Additional problems with the standard fibrin sealants stem from the transfusion risk of human cryoprecipitate (E. M. Soland et al., JAMA 274:1368-1373 (1995)), the low and variable amounts of fibrinogen in the cryoprecipitate (10-30 mg) (P. M. Ness et al., JAMA 241:1690-1691 (1979)), hypotensive responses to bovine thrombin (R. Berguer et al., J. Trauma 31:408-411 (1991)) and antibody responses to bovine thrombin (S. J. Rapaport et al., Am. J. Clin. Pathol. 97:84-91 (1992)).
The American Red Cross and others have developed plasma protein purification methods that seem to eliminate the hepatitis risk. R. F. Reiss et al., Trans. Med. Rev. 10:85-92 (1996). These products are presently being considered for approval by the Food and Drug Administration.
A dry fibrinogen-thrombin dressing (TACHOCOMB(trademark), Hafslund Nycomed Pharma, Linz, Austria) is also available for operating room use in many European countries. U. Schiele et al., Clin. Materials 9:169-177 (1992). Present formulations of this dressing use bovine thrombin. While this fibrinogen-thrombin dressing requires no premixing and is easy to use, its utility for field applications is limited by a requirement for storage at 4xc2x0 C. and the necessity for prewetting with saline solution prior to application to the wound.
It is therefore an object of the present invention to provide a hemostatic sandwich bandage that can be used for wound healing. Other objects, features and advantages of the present invention will be set forth in the detailed description of preferred embodiments that follows, and in part will be apparent from the description or may be learned by practice of the invention. These objects and advantages of the invention will be realized and attained by the compositions and methods particularly pointed out in the written description and claims hereof.
In accordance with these and other objects, a first embodiment of the present invention is directed to a hemostatic sandwich bandage for treating wounded tissue in a patient which comprises: (i) a first fibrinogen layer; (ii) a thrombin layer adjacent to the first fibrinogen layer; and (iii) a second fibrinogen layer adjacent to the thrombin layer.
A second embodiment of the present invention is directed to a hemostatic sandwich bandage for treating wounded tissue in a patient which comprises: (i) a resorbable material layer; (ii) a first fibrinogen layer adjacent to the resorbable material layer; (iii) a thrombin layer adjacent to the first fibrinogen layer; and (iv) a second fibrinogen layer adjacent to the thrombin layer.
A third embodiment of the present invention is directed to a hemostatic sandwich bandage or treating wounded tissue in a patient which comprises: (i) a first fibrinogen layer; (ii) a resorbable material layer adjacent to the first fibrinogen layer; (iii) a thrombin layer adjacent to the resorbable material layer; and (iv) a second fibrinogen layer adjacent to the thrombin layer.
A fourth embodiment of the present invention is directed to a hemostatic sandwich bandage for treating wounded in a patient which comprises: (i) a resorbable material layer; and (ii) a thrombin layer adjacent to the resorbable material layer. The resorbable material layer may also optionally contain fibrinogen.
A fifth embodiment of the present invention is directed to a hemostatic sandwich bandage for treating wounded in a patient which comprises: (i) a first resorbable material layer; (ii) a second resorbable material layer adjacent to the first resorbable material layer; and (iii) a thrombin layer adjacent to the second resorbable material layer. The resorbable material layers may also optionally contain fibrinogen.
Each layer of the inventive hemostatic bandages may also optionally contain one or more suitable fillers, binding agents and/or solubilizing agents. In addition, each of the inventive hemostatic bandages may also optionally further comprise a release layer which contains a release agent and/or a backing material.
A sixth embodiment of the present invention is directed to methods for treating wounded tissue in a patient, which comprises applying any of the inventive hemostatic sandwich bandages to the wounded tissue.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are intended to provide further explanation of the invention as claimed.
A. Definitions
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications mentioned herein are incorporated by reference.
xe2x80x9cPatientxe2x80x9d as used herein refers to human or animal individuals in need of medical care and/or treatment.
xe2x80x9cWoundxe2x80x9d as used herein refers to any damage to any tissue of a patient that results in the loss of brood from the circulatory system. The tissue may be an internal tissue, such as an organ or blood vessel, or an external tissue, such as the skin. The loss of blood may be internal, such as from a ruptured organ, or external, such as from a laceration. A wound may be in a soft tissue, such as an organ, or in hard tissue, such as bone. The damage may have been caused by any agent or source, including traumatic injury, infection or surgical intervention.
xe2x80x9cResorbable materialxe2x80x9d as used herein refers to a material that is broken down spontaneously and/or by the mammalian body into components which are consumed or eliminated in such a manner as not to interfere significantly with wound healing and/or tissue regeneration, and without causing any significant metabolic disturbance.
xe2x80x9cStabilityxe2x80x9d as used herein refers to the retention of those characteristics of a material that determine activity and/or function.
xe2x80x9cBinding agentxe2x80x9d as used herein refers to a compound or mixture of compounds that improves the adherence of one layer of the inventive hemostatic sandwich bandage to one or more different layers and/or the adherence of the components of a given layer to other components of that layer.
xe2x80x9cSolubilizing agentxe2x80x9d as used herein refers to a compound or mixture of compounds that improves the dissolution of a protein or proteins in aqueous solvent.
xe2x80x9cFillerxe2x80x9d as used herein refers to a compound or mixture of compounds that provide bulk and/or porosity to one or more layers of the inventive hemostatic sandwich bandages.
xe2x80x9cRelease agentxe2x80x9d as used herein refers to a compound or mixture of compounds that facilitates removal of an inventive hemostatic sandwich bandage from a manufacturing mold.
xe2x80x9cFoaming agentxe2x80x9d as used herein refers to a compound or mixture of compounds that produces gas when hydrated under suitable conditions.
B. Preferred Embodiments
A first preferred embodiment of the present invention is directed to a hemostatic sandwich bandage for treating wounded tissue in a patient which comprises:(i) a first fibrinogen layer; (ii) a thrombin layer adjacent to the first fibrinogen layer; and (iii) a second fibrinogen layer adjacent to the thrombin layer.
A second embodiment of the present invention is directed to a hemostatic sandwich bandage for treating wounded tissue in a patient which comprises: (i) a resorbable material layer; (ii) a first fibrinogen layer adjacent to the resorbable material layer; (iii) a thrombin layer adjacent to the first fibrinogen layer; and (iv) a second fibrinogen layer adjacent to the thrombin layer.
A third embodiment of the present invention is directed to a hemostatic sandwich bandage for treating wounded tissue in a patient which comprises: (i) a first fibrinogen layer; (ii) a resorbable material layer adjacent to the first fibrinogen layer; (iii) a thrombin layer adjacent to the resorbable material layer; and (iv) a second fibrinogen layer adjacent to the thrombin layer.
A fourth embodiment of the present invention is directed to a hemostatic sandwich bandage for treating wounded in a patient which comprises: (i) a resorbable material layer; and (ii) a thrombin layer adjacent to the resorbable material layer. The resorbable material layer may also optionally contain fibrinogen.
A fifth embodiment of the present invention is directed to a hemostatic sandwich bandage for treating wounded in a patient which comprises: (i) a first resorbable material layer; (ii) a second resorbable material layer adjacent to the first resorbable material layer; and (iii) a thrombin layer adjacent to the second resorbable material layer. The resorbable material layers may also optionally contain fibrinogen.
Each layer of the inventive hemostatic sandwich bandages may also optionally contain one or more suitable fillers, such as sucrose.
Each layer of the inventive hemostatic sandwich bandages may also optionally contain one or more suitable binding agents, such as sucrose.
Each layer of the inventive hemostatic sandwich bandages may also optionally contain one or more suitable solubilizing agents, such as sucrose.
Each layer of the inventive hemostatic sandwich bandages may also optionally contain one or more suitable foaming agents, such as a mixture of citric acid and sodium bicarbonate.
Each of the inventive hemostatic sandwich bandages may also optionally further comprise a release layer which contains a release agent. A preferred release agent is sucrose.
Each of the inventive hemostatic sandwich bandages may also further comprise a backing material on the side of the bandage opposite the wound-facing side. The backing material may be affixed with a physiologically-acceptable adhesive or may be self-adhering (e.g by having a sufficient surface static charge). The backing material may be a resorbable material or a non-resorbable material, such as a silicone patch or plastic. Preferably, the backing material is a resorbable material.
The fibrinogen employed in the inventive hemostatic sandwich bandage is preferably Topical Fibrinogen Complex (TFC), but any suitable fibrinogen, or derivative or metabolite thereof (such as fibrinopeptide A and fibrinopeptide B), may be employed as desired. A specific fibrinogen (or fibrinogen-containing composition) for a particular application may be selected empirically by one skilled in the art. The fibrinogen may also contain Factor XIII.
TFC is a mixture of human plasma proteins which have been purified to an appropriate level and virally inactivated. A preferred aqueous solution of TFC contains 100-130 mg/mL total protein, of which at least 80% is fibrinogen. Other constituents of TFC include albumin (generally about 5-25 mg/mL), plasminogen (generally about 5 mg/mL); Factor XIII (generally about 10-40 Units/mL); and polysorbate 80 (no more than 3%). The pH of TFC is generally in the range of 7.1-7.5. Suitable TFC may also contain fibronectin.
The thrombin employed in the inventive hemostatic bandage is preferably a lyophilized mixture of human plasma proteins which have been purified to an appropriate level and virally inactivated. A preferred aqueous solution of thrombin contains thrombin at a potency of about 300xc2x150 International Units/mL. Other constituents include albumin (generally about 5 mg/mL) and glycine (generally about 0.3 Mxc2x10.05M). The pH of the preferred thrombin is generally in the range of 6.5-7.1.
Additionally, in each of the embodiments of the present invention, thrombin may be replaced by any of the agents known by those skilled in the art to be activators of fibrin formation. Illustrative examples of such agents are snake venoms. A specific activator of fibrin formation for a particular application may be selected empirically by one skilled in the art.
Any suitable resorbable material known to those skilled in the art may be employed in the present invention. For example, the resorbable material may be a proteinaceous substance, such as silk, fibrin, keratin, collagen and/or gelatin, or a carbohydrate substances, such as alginates, chitin, cellulose, proteoglycans (e.g. poly-N-acetyl glucosamine), glycolic acid polymers, lactic acid polymers, or glycolic acid/lactic acid co-polymers. Specific resorbable material(s) for a particular application may be selected empirically by those skilled in the art.
Preferably, the resorbable material is a carbohydrate substance. Illustrative examples of particularly preferred resorbable materials are sold under the tradenames VICRYL(trademark) (Poly(Lactide-Co-Glycoside), a glycolic acid/lactic acid copolymer) and DEXON(trademark) (glycolic acid polymer).
The various layers of the inventive hemostatic sandwich bandage may be affixed to one another by any suitable means known and available to those skilled in the art. Preferably, the fibrinogen layer(s) and/or the thrombin layer(s) is (are) applied as a series of quick-frozen aqueous solution layers and subsequently lyophilized or freeze-dried.
In a particularly preferred embodiment of the present invention, when the inventive bandages are prepared using a mold, a release agent, such as sucrose, is applied to the mold before the first layer of the bandage being prepared. In such embodiments, the inventive hemostatic sandwich bandage further comprises a release layer, which contains said release agent, adjacent to the (i) layer and on the opposite side from the (ii) layer.
Alternatively, a physiologically-acceptable adhesive may applied to the resorbable material and/or the backing material (when present) and the fibrinogen layer(s) and/or the thrombin layer(s) subsequently affixed thereto.
In one embodiment of the inventive sandwich bandage, the physiologically-acceptable adhesive has a shear strength and/or structure such that the resorbable material and/or backing material can be separated from the fibrinogen layer and/or the thrombin layer after application of the bandage to wounded tissue. In another embodiment, the physiologically-acceptable adhesive has a shear strength such that the resorbable material and/or backing material cannot be separated from the fibrinogen layer and/or the thrombin layer after application of the bandage to wounded tissue.
Suitable fibrinogen and thrombin may be obtained from human or mammalian plasma by any of the purification methods known and available to those skilled in the art; from supernatants or pastes of recombinant tissue culture, viruses, yeast, bacteria, or the like that contain a gene that expresses a human or mammalian plasma protein which has been introduced according to standard recombinant DNA techniques; or from the fluids (e.g. blood, milk, lymph, urine or the like) of transgenic animals that contain a gene that expresses human fibrinogen and/or human thrombin which has been introduced according to standard transgenic techniques.
As a general proposition, the purity of the fibrinogen and/or the thrombin for use in the inventive hemostatic sandwich bandage will preferably be an appropriate purity known to one of ordinary skill in the relevant art to lead to the optimal efficacy and stability of the protein. Preferably, the fibrinogen and/or the thrombin has been subjected to multiple chromatographic purfication steps, such as affinity chromatography and preferably immunoaffinity chromatography, to remove substances which cause fragmentation, activation and/or degradation of the fibrinogen and/or the thrombin during manufacture, storage and/or use. Illustrative examples of such substances that are preferably removed by purification include protein contaminants, such as inter-alpha trypsin inhibitor and pre-alpha trypsin inhibitor; non-protein contaminants, such as lipids; and mixtures of protein and non-protein contaminants, such as lipoproteins.
The concentration of the fibrinogen and/or the thrombin employed in the inventive hemostatic sandwich bandage is also preferably selected to optimize both the efficacy and stability thereof, as may be determined empirically by one skilled in the relevant art. During use of the inventive hemostatic sandwich bandage, the fibrinogen and the thrombin are preferably activated at the time the bandage is applied to the wounded tissue by the endogenous fluids of the patient escaping from the hemorrhaging wound. Alternatively, in situations where fluid loss from the wounded tissue is insufficient to provide adequate hydration of the protein layers, the fibrinogen and or the thrombin may be activated by a suitable, physiologically-acceptable liquid, optionally containing any necessary co-factors and/or enzymes, prior to or during application of the hemostatic sandwich bandage to the wounded tissue.
In addition, one or more supplements may also be contained in one or more layers of the inventive hemostatic sandwich bandage, such as growth factors, drugs, polyclonal and monoclonal antibodies and other compounds. Illustrative examples of such drugs include, but are not limited to: antibiotics, such as tetracycline and ciprofloxacin, amoxicillin, and metronidazole; anticoagulants, such as activated protein C, heparin, prostacyclin (PGI2), prostaglandins, leukotrienes, antithrombin III, ADPase, and plasminogen activator; steroids, such as dexamethasone, inhibitors of prostacyclin, prostaglandins, leukotrienes and/or kinins to inhibit inflammation; cardiovascular drugs, such as calcium channel blockers, vasodilators and vasoconstrictors; chemoattractants; local anesthetics such as bupivacaine; and antiproliferative/antitumor drugs such as 5-fluorouracil (5-FU), taxol and/or taxotere; antivirals, such as gangcyclovir, zidovudine, amantidine, vidarabine, ribaravin, trifluridine, acyclovir, dideoxyuridine and antibodies to viral components or gene products; cytokines, such as xcex1- or xcex2- or xcex3-Interferon, xcex1- or xcex2-tumor necrosis factor, and interleukins; colony stimulating factors; erythropoietin; antifungals, such as diflucan, ketaconizole and nystatin; antiparasitic gents, such as pentamidine; anti-inflammatory agents, such as xcex1-1-anti-trypsin and xcex1-1-antichymotrypsin; anesthetics, such as bupivacaine; analgesics; antiseptics; and hormones. Other illustrative supplements include, but are not limited to: vitamins and other nutritional supplements; glycoproteins; fibronectin; peptides and proteins; carbohydrates (both simple and/or complex); proteoglycans; antiangiogenins; antigens; lipids or liposomes; oligonucleotides (sense and/or antisense DNA and/or RNA); and gene therapy reagents.
The following examples are illustrative only and are not intended to limit the scope of the invention as defined by the appended claims. It will be apparent to those skilled in the art that various modifications and variations can be made in the methods of the present invention without departing from the spirit and scope of the invention. Thus, it is intended that the present invention cover the modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents.
All patents and publications referred to herein are expressly incorporated by reference.